Figure 1: The NO‾/ONOO‾Cycle

Key to Figure 1: The NO‾/ONOO‾ Cycle “Players”

• Nitric oxide (NO‾) is a naturally occurring “messenger molecule” in the body and also a pro-oxidant and free radical. Depending on the amount and where it is released, NO can be either beneficial or toxic. (141-145,223)
  Nitric oxide is known to play a role in blood pressure regulation, blood clotting, immunity, digestion, the special senses (sight and smell), and possibly learning and memory. Abnormal levels of NO‾ may play a role in diseases such as atherosclerosis, diabetes, stroke, hypertension, impotence, septic shock, and long-term depression. (52,145) In ME/CSF/FM and related multi-system diseases, research suggests that excess NO‾ may be a primary contributor to long-term energy depletion and immune dysfunction. (101,141-142,223)
• Superoxide (O2‾) is a potent free radical. Like nitric oxide (NO‾), O2‾ has independent deleterious effects when expressed in excess. Superoxide reacts with NO‾ to form ONOO‾.
• OONO‾ (peroxynitrite) is a potent oxidant that damages cells. It is formed when NO‾ and O2‾ react with each other. Peroxynitrite in turn acts through multiple mechanisms to regenerate its precursors, NO‾ and O2‾. In this way, a “vicious cycle” of damage creating more damage begins.

Consequences of Superoxide (O2‾) Excess:

1.) Inflammation (130,137)
2.) Vaso-spasm (131)
3.) Endothelial dysfunction (132,134,135,138,139)
4.) Associated with retinal cell death, pulmonary hypertension, general hypertension, atherosclerosis, neurodegenerative disease, type II diabetes (73,132,134,136-140)
5.) Decreased cellular respiration (133)
6.) Cell death (133) + Consequences of Nitric Oxide (NO‾) Excess:

1.) Cellular energy depletion (97, 120)
2.) DNA damage (98-100, 118,123)
3.) Neurotoxicity, neuronal cell death and brain injury (52, 57, 58, 84,100-104,111-113, 115,123)
4.) Hypersomnolence and sleep apnea (102, 105)
5.) Lung injury (61,62,128,129)
6.) Increased pain perception and lowered pain threshold (53, 59)
7.) Lowered blood pressure (224-225)
8.) Inhibition of the methylation cycle (106, 107)
9.) Formation of carcinogenic substances (99)
10.) Increased inflammation (61, 62, 110,120,121,125,126, 130)
11.) Cytotoxicity (68,114,115,120, 123)
12.) Modification of cellular proteins (100,123)
13.) No is associated with Alzheimer’s, Arthritis, Parkinson’s, stroke, hemorrhagic shock, cancer, viral infections (57, 58, 97,98,113,115, 120,121,122,123)
14.) Damaged mitochondria (108,109,111,112, 114,115,127)
15.) Suppressed immune system (122)
16.) Assisted viral replication and pathogenesis (122, 124, 126,127)
→ Consequences of Excess Peroxynitrite (ONOO‾)

1.) Neurotoxic (72,74,76,85, 88,89)
2.) Cytotoxic (68,82-84,87,119)
3.) Increases lipid peroxidation (54,87,90,119,125)
4.) Retinal cell death (73,75,86)
5.) DNA damage (77,87,118,119,125)
6.) Decreased mitochondrial respiration (cellular oxygen)
(69,77,78,90,92,119)
7.) Increase viral replication (80)
8.) ONOO- is associated with Alzheimer’s disease, rheumatoid arthritis, atherosclerosis, lung injury, amyotrophic lateral sclerosis, HIV, multiple sclerosis, kidney damage, Parkinson’s disease, Huntington’s disease, Sjögren’s syndrome, septic shock and other diseases. (57,72,74,78,80,81,84,87,88,89,91)

Fig. 2: Independent Consequences of Increased Superoxide (O2‾ ), nitric oxide (NO‾ ) and peroxynitrite (ONOO‾ ).

Dr. Bell, one of the first physicians to recognize ME/CFS as a discrete medical condition, proposes in his book Cellular Hypoxia and Neuro-Immune Fatigue that cellular hypoxia may be the underlying factor in ME/CFS and related multi-system diseases. (146). This is consistent with the NO‾/ONOO‾ theory, because injuries of many types result in decreased oxygen (hypoxia) to the cell, thus initiating this destructive runaway cycle.

Hydroxocobalamin Breaks the NO‾ / ONOO‾ Cycle

Hydroxocobalamin (cobinamide), a unique form of vitamin B-12, is a potent nitric oxide (NO‾) scavenger. It is the only form of vitamin B12 that effectively neutralizes the NO‾ molecule. Hydroxocobalamin is the preferred form of vitamin B-12 required to break the NO‾/ONOO‾ vicious cycle of cellular damage. (147-149)

The Methylation Cycle and ME/CFS

The Methylation Cycle is a biochemical pathway required for the manufacture of DNA, RNA, phospholipids (myelin sheath of nerves), neurotransmitters, adrenal hormones and more than 100 enzymes. A fully functional methylation cycle is also required for numerous detoxification reactions. (150-157)

A defect in the methylation pathway is a second proposed mechanism in the development of ME/CFS. The research of Dr Rich van Konynenburg has been instrumental in demonstrating the intricate interrelationship between the methylation cycle and ME/CFS. (158)

Methylation defects cause reduced detoxification ability, decreased production of serotonin, dopamine, melatonin and other neurotransmitters, decreased production of adrenal hormones, increased levels of toxic homocysteine, and decreased cellular energy production. (159-163)

This reduced production of vital neurotransmitters may explain the feelings of depression and despondency that frequently strike ME/CFS victims and would explain the positive effects often achieved with the use of SSRI and other mood-altering pharmaceuticals. Unfortunately, many clinicians interpret the improvement seen with antidepressant medications as “proof” that ME/CFS is a psychiatric illness when in fact an understanding of the methylation pathway defect offers solid evidence of a biochemical basis for depression and low energy in ME/CFS.

Figure 3: The Methylation Cycle

Note the overlap between the NO‾/ONOO‾ Cycle and the Methylation Cycle where excess NO‾ blocks methionine synthase, a critical enzyme in the methylation cycle. (106, 164-167)

The methylcobalamin form of vitamin B-12 is a required nutrient in the Methylation Cycle. If any one step in the methylation cycle fails, the entire cycle fails.

Vitamin B12: Which Form is Best?

What we know as Vitamin B-12 is actually a collection of four related but different cobalt-containing molecules. Each of these forms plays a distinct role in the body as follows:

Hydroxycobalamin is a unique form of B12 that quenches excess nitric oxide (NO‾), the precursor to peroxinitrite (ONOO‾).(147-149,172-176) Hydroxocobalamine (and methylcobalamine) are also more effective at treating neurological disorders than cyanocobalamine. (168)

Hydroxocobalamin participates in detoxification, especially cyanide detoxification. Cyanide levels are typically elevated in smokers, people who eat cyanide-containing food (like cassava) and those with certain metabolic defects. Excess cyanide in the tissues blocks conversion of cyanocobalamin to methylcobalamin or adenosylcobalamin. In such instances, hydroxocobalamin is the vitamin B-12 of choice. (169-171) Hydroxycobalamin is FDA- approved as a treatment for cyanide poisoning. (214

Methylcobalamin is considered by many researchers to be the most active form of vitamin B12. (177-179) It is the requisite form of vitamin B-12 in the Methylation Cycle. (179-186). Methylcobalamin protects cortical neurons against NMDA receptor-mediated glutamate cytotoxicity.(187-188) and promotes nerve cell regeneration. (189) Methylcobalamine is the only form of vitamin B-12 that participates in regulating circadian rhythms (sleep/wake cycles). It has been shown to improve sleep quality and refreshment from sleep, as well as increased feeling of well-being, concentration and alertness. (190).

Adenosylcobalamin (dibencozide), another highly active form of vitamin B12, is essential for energy metabolism (191) and is required for normal myelin sheath formation and nucleoprotein synthesis. Deficiencies are associated with nerve and spinal cord degeneration. (192-193)

Cyanocobalamin, the most common form of B12 found in nutritional supplements, is a synthetic form of B12 not found in nature. It has the lowest biological activity and must be converted in the liver to more biologically active forms. This conversion is inefficient and some people who may not benefit from cyanocobalamine due to lack of assimilation or conversion. (194-195) However, the cyano form of B12 is needed to balance hydroxycobalamin in performing its NO-quenching function and should therefore be included in hydroxocobalamine supplements. (176)

Who is Vitamin B12 Deficient and Why?

Research shows that a much larger segment of the general population is vitamin B12 deficient than previously thought. Recent studies indicate that up to 78% of seniors are deficient. (196-197)

Irritable bowel syndrome (IBS), seen in as many as 77% of CFS patients and 78% of FM patients (198-199) is a major cause of vitamin B12 deficiency. (200) This leads one to ponder the “which came first, the chicken or egg” nature of this: are ME/CFS patients B12 deficient because of IBS, or is IBS a result of cellular or neurological insult caused by B12 deficiency?

Other high-risk groups for B12 deficiency include those who use acid-blocking or neutralizing drugs (such as Prilosec, Prevacid, Nexium and others) (201-204), drugs which impair intestinal absorption (such as Metformin, Questron and Chloromycetin) (205), and people who have had gastric surgery. (206-207) Bacterial overgrowth of the small intestine, which occurs frequently in people with ME/CFS and low stomach acid, is a predisposing factor for B12 deficiency because the bacteria themselves use vitamin B12. (208-209)

The most recent and disturbing studies suggest that vitamin B12 deficiency is more prevalent in young adults than previously thought. (210-211). One study found that vitamin B12 deficiency was similar in three age groups (26-49 years, 50-64 years, and 65 years and older), but that early symptoms were simply less apparent in the young. This study also found that those who did not take a vitamin B12-containing supplement were twice as likely to be deficient as supplement users, regardless of age. (210)

Secondly, unlike other water-soluble vitamins, B12 is stored in the liver, kidneys and other tissues. Deficiencies of B12 often appear so slowly and subtly as to go unnoticed, and blood tests for vitamin B12 levels miss early deficiency states at least 50% of the time. (212-213)

Why Vitamin B12 MUST Be Obtained From Supplements

Medical science once believed that few people were vitamin B12 deficient. This false assumption may stem from the fact that vitamin B12 is produced in the body by a normal, healthy population of bowel bacteria.

Foods are not a significant source of vitamin B12. Meat, milk, eggs, fish, and shellfish contain the highest amount of B12 but only 50% of this is absorbable even in a healthy gut. (215) Vegetarian sources of vitamin B12, such as algae, are not bio-available and do not make significant contribution to dietary vitamin B12 levels. (216)

Further, absorption is hampered by low stomach acid, IBS, and bacterial overgrowth of the small intestine — conditions which are common in ME/CFS sufferers. The US Institute of Medicine recommends that adults over 50 obtain their vitamin B12 from supplements. (14)

Oral vs. Injectable: Which is Best?

Although vitamin B12 has previously been given by injection, it is now accepted in conventional medicine that oral vitamin B12 is equally as effective as injection in treating pernicious anemia and other B12 deficient states. (214, 217-220).

According to The National Institutes of Health (NIH), oral vitamin B12 supplementation is extremely safe (221-222). It is also as effective as injections, (14,219-220) and inexpensive and more convenient compared to injection. (220)

All Roads Lead To B12: Conclusions and Recommendations

The suffering from ME/CFS and other multi-system diseases is widespread and devastating. This affliction is beginning to receive more attention, perhaps because of the activism of those affected and the dedication of ME/CFS researchers and clinicians. Current research is providing us with new insights into the underlying mechanisms of this complicated illness.

The Nitric Oxide / Peroxynitrite model (NO‾/ONOO‾) and The Methylation Cycle have emerged as two likely contributory mechanisms to ME/CFS and other multi-system diseases including Fibromyalgia (FM), Lyme Disease, Multiple Chemical Sensitivities (MCS), PTSD and Gulf War Syndrome. Deficiencies of either of two forms of vitamin B12 — hydroxocobalamin and/or methylcobalamin — play a significant role in these biochemical processes.

Since Vitamin B12 (especially the hydroxocobalamin and methycobalamin forms) offer such potential benefits for ME/CFS and other multi-system disease sufferers — without known risks — it seems reasonable to suggest that anyone suffering with ME/CFS or other multi-system illness should consider taking a supplement containing these two important forms of vitamin B12.

Furthermore, because of the balancing effect that cyanocobalamin has on hydroxycobalamin (176) and the protective and regenerative effect that adenosylcobalamin exerts on the myelin sheath of nerves (192-193), these forms should also be considered as an important part of any complete vitamin B12 supplement.

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